Last year (2005), Swan et al. reported strong associations between phthalate levels measured in the urine of mothers and altered reproductive tract development in baby boys. They found that boys with higher phthalate levels had smaller perineums, consistent with reductions in fetal exposure to testosterone. They also reported that the levels of phthalates in boys with smaller perineums were comparable to those found by CDC measurements in 25% of American women.

In this paper, Marsee et al. estimate the amount of daily exposure to phthalates that would have been necessary to cause the levels of phthalates observed in the mothers' urine reported by Swan et al.

They conclude that the levels seen in mothers in Swan's study would have been caused by exposure to phthalates approximately 100 times lower than EPA's current safety threshold for phthalates. This calculation indicates that safety standards for phathalate exposure may need to be tightened considerably.

What did they do? Marsee et al. used different two mathematical models, called 'pharmacokinetic' models, that have been developed by scientists who study the ways that chemicals are absorbed into the body, how they are metabolized once in, and where and how fast they are excreted. The models allowed Marsee et al. to estimate how much exposure would be necessary to produce the levels of phthalate metabolites measured in the mothers' urine, for four of the phthalates they included in their study: dibutyl phthalate (DBP), butylbenzyl phthalate (BBzP), diethyl phthalate (DEP) and Di(2-ethylhexyl) phthalate (DEHP).

What did they find? They ran the calculations for each of four phthalates measured in each woman sampled and then compared the median and 95 percentile of those calculations with the EPA safety standard. Their calculations indicate that women in the study were exposed to phthalates at levels far beneath the current safety thresholds established by EPA.

The table to the right summarizes the calculations made by Marsee et al., using one of the models, and their comparison to the EPA's 'reference
dose.' Results with the other model were somewhat lower for all but DEHP, which was higher.

Units are μg/kg/day

The 95th percentile estimate is particularly revealing, because it shows that 95% of women had estimated exposure levels far beneath the EPA's reference dose.

What does it mean? In their earlier study, Swan et al. found statistical associations between DBP, DEP and BBzP and altered perineum size, which they measured as anogenital distance, which correcting for the baby's overall size, they called the anogenital index. They found very strong associations between mixtures of these three and changes in the anogenital index.

These new calculations indicate that the current reference doses for phthalates may be too high to avoid adverse effects in people. If the levels in Swan et al.'s study in fact caused the altered genital development, then the standards will need to be reduced at least 100-fold, but probably more.

This conclusion is tentative, principally for two reasons:

First and most important, the earlier results by Swan et al. do not prove that phthalates reduced anogenital distance in baby boys. No epidemiological study proves causation. The Swan et al. study was relatively small, although the statistical significance of the assocation with mixtures was very high (a calculation which takes into account the sample size), and clearly warrants replication. Its plausibility was strengthened by the fact that it was based on very specific predictions from animal experiments, in which it has been proven that phthalates affect genital development. The levels of individual phthalates necessary to alter genital development in animals is higher than the levels observed in Swan's sample of women.

Second, the pharmokinetic models used to estimate exposures require a series of assumptions. The similarity between the results of the two different models is reassuring in this regard.